Polycystic kidney disease is a heterogenous group of disorders characterized by large kidneys with epithelial lined cysts along the nephron collecting ducts of the affected kidneys. In all types of cystic kidney disease, the enlargement of the cyst wall is associated with hyperplasia of renal epithelium. There are several examples of genetic predisposition to cystic disease, with the most common forms of human polycystic kidney disease (PKD) being genetically transmitted as either an autosomal dominant trait or an autosomal recessive trait. There are also several forms of acquired polycystic kidney disease. Acquired lesions are caused by broad categories of agents, such as teratogens (e.g., diphenylamine and phthalates), agents affecting metanephric development (e.g., steroid hormones such as glucocorticoids), and as a consequence of loss of renal mass (as seen in end-stage renal disease). Even in kindreds with a defined genetic mutation, there is broad expression of the clinical phenotype. An example of this is a family with autosomal recessive PKD in several siblings, where the onset of renal failure was variable in the child and adolescent years. It is also well established that autosomal dominant PKD is asymptomatic in half of the kindred who are genetically affected, while approximately 1/6 go to renal failure. Moreover, the genetic trait does not discriminate the phenotypic variation of gender. The observation that the genetics are only one part of the clinical phenotype of PKD has created interest in looking at the pathophysiology of cystic disease and progression in the hope of finding modifying agents.
Currently, however, there is no effective treatment for Polycystic Kidney Disease (PKD), one of the three leading causes of end stage renal failure in humans (Canadian Organ Replacement Register; p. 95 [1990]). Although PKD simulates Mendelian inheritance, there is evidence that phenotypic expression of PKD involves genetic heterogeneity and multifactorial inheritance, including nongenetic factors.
The ready availability of non-invasive imaging techniques of ultrasound, computerized axial tomography and nuclear magnetic resonance imaging has confirmed that PKD is a common human ailment (Ogborn et al., Pediatr. Res., 2: 123-146 [1988])). One in 1100 fetuses are affected and adult prevalence may be as high as 1 in 220. (Danovitch, In Cystic Diseases of the Kidney, Gardner, K D (ed), John Wiley & Sons Inc., Toronto, p. 125-150, (1975)); (Campbell, Clin. Pediatr. Urol., Chapter 3: 181-186 (1951)). The probability of developing symptomatic renal insufficiency varies with age and pattern of presentation. It is known that both the number and size of cysts increase throughout life in this form of PKD, often starting in childhood. In the most common "adult" or dominantly inherited PKD (ADPKD), end-stage renal failure has been described in patients ranging from infancy (Taitz et al. Arch. Dis. Child., 62: 45-49 [1987]) to the ninth decade (Churchill et al., Kid. Int., 26: 190-193 [1984]). In this situation the cysts appear in the kidney in such large numbers that the renal parenchyma is destroyed thus contributing to end-stage renal failure.
The other major form of PKD is "infantile" or recessive PKD (ARPKD), which also has a wide range of clinical presentation (Zerres, Pediatr. Nephrol. 1: 397-404 (1987)). ARPKD can first be detected during the second trimester of pregnancy. Unfortunately, therapeutic abortion is the only prenatal intervention currently available.
The broad clinical spectrum of PKD suggests a complex interaction of genetic and other factors. Schimke has speculated that all forms of PKD may represent variable expression of common genes under different environmental influences (Schimke, Problems in Diagnosis and Management of Polycystic Kidney Disease, Grantham J J and Gardner K D (eds.) PKR Foundation, Kansas City, 49-69, (1985)). This concept is supported by much of the available experimental evidence. Wirth et al., (in Hum. Genet, 77: 221-222 (1987)), although not excluding such a concept, consider that family pedigrees and linkage studies confirm that ARPKD and ADPKD are mutations at distinct genetic loci, rather than being allelic mutations at the same locus.
Indeed, the locus of one gene marker of PKD, i.e., PKD1, has been mapped to chromosome 16 by Reeders et al. (Nature, 317:542-544 (1985)) and linked with biochemical polymorphisms and anonymous restriction fragment length polymorphism (RFLP) markers, thus permitting detection of asymptomatic individuals in the family (see also Reeders, Pediatr. Nephrol., 1:405-410 (1987)). However, the gene(s) responsible for ADPKD in some families is/are not linked to the chromosome 16 locus (Kimberling et al., NEJM, 319(14):913-918 (1988)). This genetic heterogeneity suggests that genetic screening must be approached with caution (Germino et al., Am. J. Hum. Genet., 46:925-933 (1990)); Parfrey et al., NEJM, 323:1085-1090 (1990)).
In addition to the genetic heterogeneity of PKD, these traits show variable expressivity. The pathological features of the various forms of PKD exhibit overlaps, such as hepatic fibrosis, and distinguishing features, such as liver cysts in ADPKD. In addition, liver cystic disease may occur on its own without kidney cysts (Grunfeld et al., Advances in Nephrology, 14:1-20 (1985)). There is currently an inability to diagnose this disease either early in its progression or even at all. This situation is supported by the greater incidence of PKD seen at autopsy rather than in clinical practice.
The ethical and practical difficulties of studying induction of renal cysts in humans have encouraged the study of animal models. These models are well characterized in recent reviews (see, for example, Ogborn et al., Pediatr. Res., supra; Brenner, J. Am. Soc. Nephrol., 1:127-139 (1990); Avner et al., in: The Cystic Kidney. Eds. Gardner K D, Bernstein J, 55-98 (1990)). Reproducible models of PKD include those induced by organic chemicals--specifically diphenylamine, diphenylthiazole and nordihydroguaiaretic acid and those induced by the administration of glucocorticoids (Avner et al., supra) and (Perey et al., Science, 158: 494-496 (1967)).
Accordingly, there is still a need in the art for effective methods for the diagnosis and treatment of each of the various forms of polycystic kidney disease.